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Future Use of Selective Estrogen Receptor Modulators and Aromatase Inhibitors I

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Future Use of Selective Estrogen Receptor Modulators and Aromatase Inhibitors I 4402s Vol. 7, 4402s-4410s, December 2001 (Suppl.) Clinical Cancer Research Future Use of Selective Estrogen Receptor Modulators and Aromatase Inhibitors I Anthony Howell 2 The two groups of endocrine therapies for which there has been CRC Department of Medical Oncology, University of Manchester, the greatest development recently are the SERMs 3 and the AIs. Christie Hospital, Manchester M20 4BX, United Kingdom SERMs Available or in Development The first SERMs to be used clinically were pharmacolog- Abstract ical doses of estrogen analogues, for example, DES (1), dienes- Selective estrogen receptor modulators (SERMs) may trol (2), and ethinylestradiol (3). Randomized trials comparing act as estrogens or antiestrogens depending on the cell and high-dose estrogens with tamoxifen showed them to be equally tissue targets. The triphenylethylene SERMs are repre- active (reviewed in Ref. 3). After long-term follow-up, the sented by tamoxifen and toremifene and a new agent with a largest trial of this type showed a survival advantage for DES novel carboxylic acid side chain (GW5638). Because of compared with tamoxifen (4). We recently reported a study of isomerization in the triphenylethylene molecule, "fixed DES involving 30 patients who had had on average four previ- ring" SERMs were introduced. The major one in develop- ous endocrine therapies. Thirty percent of patients responded to ment is the benzothiophene arzoxiphene (LY353381), which DES for a median period of 49 weeks, suggesting that high-dose is now in Phase llI clinical trial versus tamoxifen. A fourth estrogen therapy may well have been abandoned prematurely as group of SERMs is based on the estrogen molecule and an endocrine treatment (5). comprises the so-called "pure" antiestrogen ICI 182,780 High-dose estrogens were largely replaced by tamoxifen as (fulvestrant, Faslodex) and a new oral analogue just entering soon as the latter was shown to be potentially equally active but trials, SR16234. The steroidal aromatase inhibitors [AIs less toxic (6). Several attempts have been made to introduce (40H androstenedione and exemestane)] inactivate aro- more active analogues of tamoxifen, but randomized clinical matase, whereas the triazole AIs (anastrozole and letrozole) trials and Phase II studies have not shown superiority for the inhibit the enzyme via the heme prosthetic group. Thus, analogues idoxifene, droloxifene, or TAT 59 compared with there are two groups of AIs that show relative non-cross- tamoxifen, and these have therefore been abandoned for breast resistance in advanced breast cancer and four groups of cancer treatment (7). Toremifene remains available but shows SERMs that also show a high degree of non-cross-resistance. no advantage over tamoxifen for either adjuvant treatment (8) or With six different treatments and six or more clinical situ- the treatment of advanced disease (9). A new triphenylethylene ations (prevention, neoadjuvant, adjuvant, and first- and (GW5638), which may be more active than the others because second-line treatments for advanced disease) in which they of a novel carboxylic acid side chain, looks promising in pre- may be used, the possible combinations of treatment are clinical studies and is currently entering clinical trials (Refs. 10 enormous. At present, we have few clinical pointers to op- and 11; Fig. 1). timal sequence of treatments. Now that most of the appro- Isomerization around the double bond in the triphenyleth- priate comparative trials have been performed, it may be the ylene molecule was thought to be problematical, and thus a time to initiate novel approaches. These include alternating series of so-called "fixed ring" structures have been introduced, and sequential treatments, preferably with treatments including raloxifene, EM800 (EM652 is the metabolite), and changed before overt progression occurs. arzoxifene (LY353381). The activity of these agents in Phase II trials in advanced breast cancer is shown in Table 1. Raloxifene Introduction and EM800 are moderately active but have been withdrawn Although endocrine therapy has been in use clinically for from development for breast cancer treatment, whereas arzox- over 100 years, we still have a great deal to learn concerning the ifene (formerly known as SERM III) looks promising and is in optimal way to use this modality for breast cancer, not only a Phase III trial versus tamoxifen as first-line therapy in ad- because the appropriate trials to determine the best approach to vanced disease. A recent Phase I/II study suggests that arzox- treatment have not all been performed to date, but also because ifene may be non-cross-resistant with tamoxifen, although more new endocrine agents are being constantly introduced that re- data are required to be certain (12). Wyeth-Ayerst also have a quire additional studies on how to integrate the new with the old. fixed ring SERM in early clinical development (ERA-923). Wakeling and Bowler (13) developed the estrogen ana- Presented at the First International Conference on Recent Advances and Future Directions in Endocrine Therapy for Breast Cancer, June 3 The abbreviations used are: SERM, selective estrogen receptor mod- 21-23, 2001, Cambridge, MA. ulator; AI, aromatase inhibitor; DES, diethylstilbestrol; ER, estrogen 2 To whom requests for reprints should be addressed, at CRC Depart- receptor; CR, complete response; PR, partial response; SD, stable dis- ment of Medical Oncology, University of Manchester, Christie Hospital, ease; E2, estradiol; WR, withdrawal response; HRT, hormone replace- Wilmslow Road, Withington, Manchester M20 4BX, United Kingdom. ment therapy. Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2001 American Association for Cancer Research. Clinical Cancer Research 4403s OH High dose OH 'Oestrogens' ~ OH H04,~l~J~ H Stllboestrol Ethinyloestradiol / CO2H ~N~ O Triphenyl ethylenes CI Tamoxifen Toremlfene GW 5638 'Fixed ring' HO~ OH Raloxifene (LY 156,758) EM 652 (SCH 57068) Arzoxlfene (LY 353,381) H2CO~.~ R OR.L "-.~lb Oestradiol .~T T C,I~0, ~o "-~""" ""sK analogues HO 0II HO SK-{CH~,-N-CH-CH-IOH2).- 80~-1CH2)5- E I I I ICl 182,780 SR 16234 ZK-191703 Fig. 1 Structures of compounds in use or in clinical development in the four classes of SERMs described in the text. Table I First- and second-line treatment with "fixed ring" compounds EM-800 (Ref. 40) Raloxifene (Ref. 41) Arzoxifene (Ref. 42) Arzoxifene (Ref. 12) (SCH57050) 20 or 40 mg (LY156758) 300 mg (SERM III) (LY353381) 20-50 mg First-line therapy CR 1 0 28 0 PR 5 4 8 SD 10 3 t7 8 PD 27 14 43 Total response 16/43 (37%) 7/21 (33 %) 45/88 (51%) 16/49 (33 %) Second-line therapy (prior tamoxifen) 43 6 0 14 All responded logue ICI 182,780 (fulvestrant, Faslodex) as a new class of anastrozole as second-line therapy for advanced breast cancer antiestrogen because it was felt that to pursue the development (14-16). The latter results are promising because all patients in of analogues of triphenylethylenes as breast cancer treatment these two Phase III trials had been treated previously with would not be productive. ICI 182,780 (Fig. 1) has been shown tamoxifen. The results of a trial of tamoxifen versus ICI 182,780 to be non-cross-resistant with tamoxifen and to be equivalent to as first-line therapy for advanced disease will be available later Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2001 American Association for Cancer Research. 4404s SERMs and AIs Table 2 Non-cross-resistance between classes of SERMs Table 3 Non-cross-resistance between classes of AIs Classes of SERMs Classes of AIs Pharmacologic estrogens Nonsteroidal--anastrozole--letrozole Triphenylethylenes--tamoxifen Steroidal---4OH androstenedione---exemestane Fixed ring--Arzoxifene (SERM3) Examples of non-cross-resistance between classes Steroidal--ICI 182,780 Anastrozole --> 4OH (Ref. 45) Examples of non-cross resistance between classes Letrozole ~ 4OH (Ref. 45) TAM ---->ICI 182780 (Ref. 14) Anastrozole ~ Exemestane (Ref. 44) TAM ~ Arzoxifene (Ref. 43) TAM ----> Stilbestrol (Ref. 4) A B o o 100--~ 85.2% Steroidal A! 1~1761 OH CH 2 Formestane Exemestane 60-1 .... ~ 62.7% a N-N 40- N N-N NA+B 43.7% 35.9% 500 Nonsteroidal AI CH H~ ~J~ 20 NC-CHsI -,~ CH.= t-CN HO CN 0 Anastrozole Letrozole 0 5 lb 1st 2 ~ 3 rd Years Line of Therapy Fig. 2 Two classes of modern AIs: steroidal and nonsteroidal Als. Fig. 3 A, 10-year results of the effectiveness of 5 years of adjuvant tamoxifen on relapse-free survival. Just over one-third of relapses are prevented by tamoxifen. B, estimated "clinical benefit" (CR + PR + SD 6/12) after first-, second-, and third-line endocrine therapies for ad- this year and are awaited with great interest. Other estrogen vanced disease. analogues entering clinical trials are SR16234 and ZK191703, which look promising in preclinical studies and, unlike ICI 182,780, are said to be p.o. bioavailable (Fig. 1). Thus, we have four groups of SERMs available for breast Many clinical studies indicate that SERMs and AIs show cancer treatment. These are high-dose estrogens (particularly limited cross-resistance. This, together with evidence of non- DES), triphenylethylenes (tamoxifen), the fixed ring structures cross-resistance within the SERM and AI classes, indicates that (particularly arzoxiphene), and steroidal compounds (particular- we have potentially a large number of therapeutic options to ly ICI 182,780). There is strong evidence from clinical trials that explore for the treatment of all stages of breast cancer. However, DES and ICI 182,780 are non-cross-resistant with tamoxifen, with six groups of agents (perhaps seven if ovarian ablation is and there is some evidence that arzoxifene is non-cross-resistant included) and six or seven clinical scenarios (prevention, neo- with tamoxifen (Table 2). Non-cross-resistance is probably re- adjuvant, adjuvant, and first-, second-, and third-line therapy for lated to differences in conformation of the ER induced by the advanced disease), the problem of finding the optimal sequences SERMs of each class and is of great importance clinically or combinations of endocrine agents is enormous.
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